EP1155686A1 - Use og manganese in the treatment of wrinkles - Google Patents

Abstract

Cosmetic treatment for the treatment of lines and wrinkles, by application of a composition containing manganese.

Description

The present invention relates to the use of an effective amount of the manganese or its salts in a composition or for the preparation of a composition, the manganese or the composition being intended to loosen and / or relax the skin and / or subcutaneous tissue, in particular with a view to treating wrinkles and fine lines on the skin.

Women, and even men, currently tend to want appear young as long as possible and therefore seek to fade the marks of aging of the skin, which are reflected in particular by wrinkles and fine lines. In this regard, advertising and fashion report products intended to keep glowing and wrinkle-free skin for as long as possible, marks of young skin, especially since the physical appearance acts on the psyche and / or morale.

Until now, we treated wrinkles and fine lines with cosmetic products containing active ingredients which act on the skin, for example by moisturizing or improving its cell renewal or by promoting the synthesis of collagen that makes up the skin tissue. But, to date we do not know how to act on wrinkles by acting on the contractile elements present in the skin.

Thus, it is known that the facial skin muscles are under the control of motor nerve afferents of the facial nerve and that, moreover, the partitions interlobulars of the hypodermis contain within them fibers which constitute striated muscle tissue (panniculus carnosus). On the other hand, it is also known that a subpopulation of dermis fibroblasts, called myofibroblasts, has contractile characteristics common to the muscle tissue.

Calcium is the final messenger of muscle contraction. The contraction-relaxation cycle is due to variations in the concentration of cytoplasmic calcium from 10 ^-8 to 10 ^-5 M in the contractile cell.

In the muscle at rest, the intracellular concentration of free calcium remains below 10 ^-8 M although the extracellular concentration is 10,000 times higher and that the force represented by the gradient of electrochemical potential tends to make calcium penetrate into the cell. This state of rest is due to the low permeability of the cell membrane for calcium and to the activity of various mechanisms which sequester calcium or expel it from the cell.

Various cytoplasmic proteins, in particular parvalbumin thus have the ability to bind calcium. Among the intracellular organelles, the reticulum endoplasmic can accumulate and release calcium under conditions compatible with physiological regulation.

The elevation of calcium levels in the cytoplasm of the muscle cell allows activation of the contractile machinery. Entry of calcium into the compartment intracellular (depolarization) contributes to the reduction of the potential difference between outside and inside and thus makes the cell more excitable.

Indeed, the depolarization of the transverse tubules (invagination of the membrane cell) that spreads to the longitudinal tubules (sarcoplasmic reticulum) induces the momentary release of intracellular calcium by the latter. In presence of calcium the contractile proteins of the striated muscle present a ATPase activity which provides the energy necessary for contraction.

Conversely, the relaxation of the striated muscle appears following the fixation of ATP on contractile proteins. The intracellular calcium then re-enters the intracellular compartment and its concentration becomes close to a value of 10 ^-8 M.

Furthermore, it has been shown that the botulinum toxin, originally used to treat spasms, could act on states of muscle spasticity (see A. Blitzer and al., Arch. Otolaryngol. Head Neck Surg., 1993, 119, pages 1018-1022) and on glabella lines which are inter-eyebrow lines (see J.D. Carruters et al., J. Dermatol. Surg. Oncol., 1992, 18, pages 17 to 21). As a result, it is possible to act on the muscular contractile component of wrinkles (especially at the level of the motor plate which corresponds to the nerve-muscle junction).

In the peripheral nervous system, the junction between a nerve and a muscle constitutes the neuro-muscular plate, upstream of which is the path efferent nerve called the motor neuron. In addition, cell membranes of each nerve fiber also have many ion channels, and in particular calcium channels, capable of allowing the element to pass through corresponding in ionic form, in this particular case calcium.

We thus understand the important role of calcium and the regulation of its intracellular concentration in the phenomena of contraction / relaxation muscle whether these phenomena are pre or post junction nerve cell / non-nerve cell (myocytes, myofibroblasts ...).

Regulation of the intracellular concentration of calcium is only possible because the efflux of calcium corrects the influx. This can only be ensured by an expulsion of cellular calcium by one or more mechanisms capable of overcoming the gradient of electrochemical potential mentioned above.
Two types of mechanism can intervene: a calcium pump which actively expels cations at the expense of ATP hydrolysis and a passive movement of calcium through different channels (depending on the calcium gradient intra and extracellular). In most cells, the ATP-dependent calcium pump works more efficiently in the presence of calmodulin, which increases its affinity.

In order to better describe the changes in calcium permeability, it is currently usual to consider that this permeability corresponds to the opening of membrane calcium channels, channels operated by variations of membrane potential (VOC) or activation of membrane receptors (ROCK). To date, six VOC types of calcium channels (L, N, T, P, Q, R) have been identified.

We therefore understand from the above that the contraction or hypercontraction of certain facial muscles result in the appearance of wrinkles. This activation muscle is itself partly induced by a variation in calcium flow at the through transmembrane calcium channels.

Now the plaintiff has now discovered after numerous clinical tests, that the contractile muscle fiber, which is under the direct control of the influx neuro-motor, plays an essential role in the formation of wrinkles and that the modulation of neuro-motor influx and control of fiber contraction muscles, play an essential role in the formation of wrinkles. So the modulation of motor contraction not only reduces wrinkles but also fine lines and also has a "smoothing" effect on the microrelief skin. She also found that the skin and subcutaneous tissues contain calcium channels, which so far has not been considered.

Thus, the applicant proposes to act on the calcium channels of the skin tissues and subcutaneous to relax or relax the tissues, and thus reduce wrinkles and fine lines.

As early as 1965, work was carried out by T. Godfraind in order to investigate the mechanisms by which certain medicinal substances inhibited the contractile response to several vasoactive agents. The hypothesis proposed was that the permeability of the membrane to calcium could be inhibited by pharmacological agents, which would constitute the common mechanism on which polyvalent antagonists would act.
The simplest experimental technique, showing that a pharmacological agent is capable of inhibiting the entry of calcium, consists in preincubating a smooth muscle in a physiological solution devoid of calcium, in depolarizing it in a solution rich in KCI and gradually increase the concentration of calcium in the infusion solution. This causes an increase in muscle tension, the value of which increases to a maximum depending on the concentration of calcium. When this protocol is repeated in the presence of a substance supposed to inhibit the entry of calcium, as was done for the first time with cinnarizine, the contractile responses are inhibited in a dose-dependent manner. A similar concept has been applied to describe the action of verapamil on the heart. Verapamil was first considered as a β-blocker, its action is more complex since it exerts an inhibitory action on the excitation-contraction coupling. On the papillary muscle, verapamil abolishes the contraction by modifying the action potential very slightly. It is this observation that leads to consider verapamil as a calcium antagonist.

Manganese is a very widespread metal on the surface of the earth's crust.
It belongs to the Vlla group of Mendeleev, its atomic number is 25, its atomic weight is 54.93. Manganese has several valences (1 to 7), the di- and trivalent forms are those which are biologically the most active.

Manganese is widely used in the metallurgical industry, in the manufacture of dry batteries and as a dye.

The plants are all rich in Mn: particularly the seeds (around 7 µg / g), nuts (about 17 µg / g) and tea. Fruits (about 1 µg / g) and vegetables (about 2.5 µg / g) are less rich, but their rate is still very high by compared to food of animal origin (meat: about 0.20 µg / g, fish: about 0.05 µg / g).

Conversely in animals, especially humans, this metal is not found than trace.

• la coagulation ;
• la thermogenèse (par son action sur le système thyroïdien)
• l'immunité, où le manganèse semble être nécessaire à une synthèse correcte des anticorps ;
• la reproduction, sa carence entraínant une baisse de fertilité des femelles, et des mâles, peut-être à cause de l'action limitante du manganèse sur la synthèse du cholestérol et de celle des précurseurs des hormones sexuelles.

Its biological role is however very important and even, if the harmful effects of a deficiency have not been irrefutably observed in humans, the consequences of the deficits examined in animals show that this metal is involved in many metabolisms. But, even today, knowledge on the intimate biochemical mechanisms of this metal remains very fragmentary.
Manganese has been implicated in many metabolisms

• coagulation;
• thermogenesis (by its action on the thyroid system)
• immunity, where manganese appears to be necessary for the correct synthesis of antibodies;
• reproduction, its deficiency causing a decline in fertility of females, and males, perhaps because of the limiting action of manganese on the synthesis of cholesterol and that of the precursors of sex hormones.

• l'activation de nombreuses enzymes.
  Le manganèse est un métal qui active de nombreuses enzymes et lectines. Il intervient soit comme un élément dissociable, soit en faisant partie intégrante de la structure de l'enzyme (métalloenzymes).
• son activité inhibitrice vis-à-vis des canaux calcium.
  Le signal interne d'activation d'une cellule est souvent déclenché par une modification des concentrations intracytoplasmiques du calcium. Ce dernier se fixe sur des protéines (calmoduline), qui vont à leur tour activer des kinases.
  Le calcium sert à la transmission de l'influx nerveux, à la stimulations de certaines cellules sécrétantes, il déclenche les changements de forme de la plaquette au début de son activation, etc.

Two properties explain part of the pathophysiological role of manganese:

• activation of many enzymes.
  Manganese is a metal that activates many enzymes and lectins. It intervenes either as a dissociable element, or by forming an integral part of the structure of the enzyme (metalloenzymes).
• its inhibitory activity with respect to calcium channels.
  The internal activation signal of a cell is often triggered by a change in intracytoplasmic calcium concentrations. The latter binds to proteins (calmodulin), which in turn activate kinases.
  Calcium is used for the transmission of nerve impulses, for stimulation of certain secreting cells, it triggers changes in the shape of the platelet at the start of its activation, etc.

Manganese blocks the penetration of calcium into the cytoplasm in numerous cells with secretory activity (pancreas for example), or electrical; he notably inhibits the exit of neurotransmitters at the level of the plaque motor. Manganese has an inhibitory action on the stimulation of lymphocytes B and T, if added to the medium, very soon after the mitogen.

For a substance to be recognized as a calcium channel blocker, otherwise called in the calcium antagonist text, it must be able to decrease the intracellular calcium concentration or decrease the binding of calcium to intracellular proteins such as calmodulin, as is notably described for example, by Galizzi, JP et al, J. Biol. Chem. 1987, 262 p 6947 or Y. Okamiya et al, Eur. J. Pharmacol. 1991, 205 , p 49 or JA Wagner et al, J. Neurosci. 1988, 8 , p 3354 or HR Lee et al , Life Sci. 1984, 35 p 721 or Schoemaker H. and Lauger S. Eur. J. Pharmacol. 1985, 111 p 273 or also IJ Reynolds et al , J. Pharmacol. Exp. Ther. 1986, 237 p 731.

A substance is recognized as relaxing within the meaning of the invention when it shows a relaxation effect on contracted muscle tissue and / or shows a inhibitory effect in an experimental nerve-muscle junction model (plaque motor) in particular in the model described by W. Steinbrecher in: Electrodes for stimulation and bioelectric potential recording, Ed. Biomerstechnich, 1988, pages 96-98.

Manganese or its salts responds well to these definitions.

As previously indicated, the plaintiff proposes to act on the canals calcium to relax or relax the tissues, thereby reducing wrinkles and fine lines. For this, it offers the use of manganese whether it is in the form ionic or in the form of salt or in the form of natural, plant or microorganisms, particularly bacteria, rich in manganese.

Thus, the present invention relates to the use in a composition or for the preparation of a composition, in a physiologically medium acceptable, of an effective amount of manganese or at least one of its salts, the manganese or the composition being intended to relax and / or relax the tissue skin and / or subcutaneous.

The invention also relates to the use in a composition or for the preparation of a composition, in a physiologically acceptable medium, an effective amount of natural, plant or microorganism extracts, particularly bacterial, rich in manganese or manganese salt, the extract or composition being intended to relax and / or relax the skin tissue and / or subcutaneous.

By manganese salts is meant according to the invention the organic salts or manganese inorganics.

As organic salts which can be used according to the invention, mention may be made of gluconate manganese or manganese carbonate or manganese acetate or manganese citrate or manganese oleate or manganese oxalate.

As inorganic manganese salts, mention may be made of mineral salts such as manganese chloride or manganese borate or manganese nitrate or manganese phosphate or manganese sulfate.

In addition, in the text, unless otherwise indicated, the use of the term manganese should be understood to mean both manganese under ionic form, in the form of salts or in the form of natural, plant or microorganisms, particularly bacteria, rich in manganese.

By physiologically acceptable medium is meant compatible with the skin, the scalp and / or mucous membranes.

Another subject of the invention is the use, in a composition or for the preparation of a composition, in a physiologically acceptable medium, of an effective amount of manganese, the manganese or the composition being intended to smooth the skin.

Yet another object of the invention is the use, in a composition or for the preparation of a composition, in a physiologically acceptable medium, of an effective amount of manganese, the manganese or the composition being intended to attenuate and / or erase the micro-relief of the skin.

In particular, the subject of the invention is the use, in a composition or for the preparation of a composition, in a physiologically medium acceptable, effective amount of manganese, manganese or composition being intended to combat, curatively and / or preventively, wrinkles and fine lines on the skin.

This use is particularly effective in reducing wrinkles and fine lines.

More particularly relaxation and / or sagging of the skin tissue and / or subcutaneous corresponds to a relaxation or a muscular relaxation.

The effective amount of manganese usable according to the invention is of course depending on the desired effect and can therefore vary to a large extent.

To give an order of magnitude, it is possible according to the invention to use the manganese in an amount representing from 0.0001% to 10% of the total weight of the composition and preferably in an amount representing from 0.001% to 5% of the total weight of the composition.

Of course when, according to the invention, a natural, vegetable or microorganisms, particularly bacteria, rich in manganese, humans trade knows how to adapt the amount of extract to be used in order to ultimately use the manganese in the amounts set out above.

As natural extracts rich in manganese which can be used according to the invention, it is possible to cite nut extracts or tea extracts.

The compositions of the invention are intended for cosmetic applications or dermatological. Preferably, the compositions of the invention are intended for cosmetic applications.

The uses according to the invention are cosmetic because they aim to modify appearance of the person.

The compositions according to the invention can be in all forms galenics normally used for topical, injectable or oral.

The composition according to the invention can be applied either locally, that is to say topically, or by subcutaneous and / or intradermal injection, or still orally.

Preferably according to the invention, the composition is applied topically.

The amounts of the various constituents of the compositions according to the invention are those conventionally used in the fields under consideration and are appropriate to their galenical form.
For topical application, the compositions of the invention comprise a medium compatible with the skin. These compositions can be in particular in the form of aqueous, alcoholic or hydroalcoholic solutions, gels, water-in-oil or oil-in-water emulsions having the appearance of a cream or a gel, of microemulsions, aerosols, or in the form of vesicular dispersions containing ionic and / or nonionic lipids. These dosage forms are prepared according to the usual methods of the fields considered.

These compositions for topical application can in particular constitute a protective, care composition for the face, for the neck, for the hands or for the body (for example day creams, night creams, creams or oils sunscreen, body milk), a makeup composition (for example complexion) or an artificial tanning composition.

When the composition of the invention is an emulsion, the proportion of fatty substances that it contains can range from 5% to 80% by weight, and preferably from 5% to 50% by weight relative to the total weight of the composition. Fats and emulsifiers used in the composition in the form of an emulsion are chosen among those conventionally used in the cosmetic field or pharmaceutical.

As fatty substances which can be used in the invention, mention may be made of mineral oils (petroleum jelly), vegetable oils (liquid fraction of shea butter) and their hydrogenated derivatives,. animal oils, synthetic oils (perhydrosqualene), silicone oils (dimethylpolysiloxane) and oils fluorinated. As other fatty substances, mention may also be made of fatty alcohols (alcohol cetyl, stearyl alcohol), fatty acids (stearic acid) and waxes.

The emulsifiers may be present, in the composition, in a proportion ranging from 0.3% to 30% by weight, and preferably from 0.5 to 30% by weight, per relative to the total weight of the composition.

In known manner, the composition of the invention may also contain usual adjuvants in the corresponding fields, such as gelling agents hydrophilic or lipophilic, preservatives, antioxidants, solvents, perfumes, fillers, filters and coloring matters. Furthermore, these compositions can contain hydrophilic or lipophilic active agents. Quantities of these various adjuvants or active agents are those conventionally used in the cosmetic or pharmaceutical field, for example from 0.01% to 20% of the total weight of the composition. These adjuvants or these active ingredients, depending on their nature, can be introduced into the fatty phase, into the aqueous phase and / or into lipid vesicles.

Among the active ingredients which the compositions of the invention may contain, it is possible to in particular mention the active agents having an effect on the treatment of wrinkles or fine lines, other than manganese, and in particular keratolytic active ingredients. Through keratolytic, we mean an active ingredient with desquamating and exfoliating properties or exfoliating, or an active ingredient capable of softening the stratum corneum.

Among the active ingredients having an effect on the treatment of wrinkles or fine lines that may contain the compositions of the invention, there may be mentioned for example alverine, channel openers chlorine hydroxy acids and retinoids.

The hydroxy acids can be, for example, α-hydroxy acids or β-hydroxy acids, which can be linear, branched or cyclic, saturated or unsaturated. The hydrogen atoms of the carbon chain can, in addition, be substituted by halogens, halogenated, alkylated, acylated radicals, acyloxylated, carbonylated or alkoxylated alkoxy having from 2 to 18 carbon atoms.

The hydroxy acids which can be used are in particular glycolic acids, lactic, malic, tartaric, citric, 2-hydroxy alkanoic, mandelic, salicylic acid, as well as their alkylated derivatives such as n-octanoyl-5-salicylic acid, n-dodecanoyl-5-salicylic acid, n-decanoyl-5-salicylic acid, n-octyl-5-salicylic acid, n-heptyloxy-5 or -4-salicylic acid, 2-hydroxy-3-methylbenzoic acid, or their alkoxylated derivatives such as 2-hydroxy-3-methoxybenzoic acid.

The retinoids may especially be retinoic acid (all-trans or 13-cis) and its derivatives, retinol (vitamin A) and its esters such as retinol palmitate, retinol acetate and retinol propionate, and their salts.

These assets can be used in particular at concentrations ranging from 0.0001% to 5% by weight relative to the total weight of the composition.

The subject of the invention is also a method of cosmetic treatment of wrinkles and / or fine lines, consisting in applying a cosmetic composition to the skin comprising in an physiologically acceptable medium, an effective amount manganese.

The cosmetic treatment process of the invention can be implemented in particular by applying the cosmetic composition as defined above, according to the usual technique for using these compositions. For example : application of creams, gels, serums, lotions, cleansing milks or anti-sun compositions on the skin or compositions for spray.

The following examples and compositions illustrate the invention without limiting it not at all. In the compositions the proportions indicated are percentages by weight, unless otherwise stated.

Example 1 :

Manganese gluconate and manganese chloride activity in a nerve / muscle junction model (motor plate) obtained in a phrenic nerve preparation / isolated diaphragm: search for a muscle relaxant effect:

The phrenic nerve and the diaphragm are carefully isolated and placed in a 50 ml tank filled with survival liquid (Krebs Henseleit liquid) maintained at a temperature of 37 ° C and oxygenated using a mixture of oxygen 95 % and CO ₂ 5%.

The diaphragm tension variations are then recorded with a initial preload of several grams.

After a 30-minute relaxation period, the diaphragm is stimulated indirectly through the phrenic nerve.

On each preparation, the effect of the products to be tested was first evaluated on the contractions induced by indirect stimulation via stimulation on the phrenic nerve (0.1 to 7 volts, 0.3 ms, 0.1 Hz) at increasing and cumulative concentrations of 10 ^-6 M to 10 ^-3 M.

Results obtained in the motor plate model with the 2 manganese salts. Product Concentration % inhibition (indirect stimulation) Manganese gluconate (n = 2) 10 ^-3 M 25% MnCl ₂ 10 ^-3 M 10%

Example 2: examples of compositions according to the invention.

Composition 1: Anti-wrinkle care lotion for the face Manganese gluconate 1.50% Antioxidant 0.05% Conservative 0.30% Ethanol (solvent) 8.00% Water qs 100% The lotion obtained acts on wrinkles during repeated use (twice daily application for one month). Composition 2: Gel for facial care Manganese chloride 0.50% Hydroxypropylcellulose 1.00% Conservative 0.30% Ethanol (solvent) 15.00% Antioxidant 0.05% Water qs 100% The gel obtained acts on wrinkles. It can be applied daily morning and evening for a month. Composition 3: Face care cream (oil-in-water emulsion) Manganese gluconate 0.50% Glycerol stearate (emulsifier) 2.00% Polysorbate 60 (Tween 60 sold by ICI) (emulsifier) 1.00% Stearic acid 1.40% Triethanolamine (neutralizer) 0.70% Carbomer (Carbopol 940 sold by Goodrich) 0.40% Liquid fraction of shea butter 12.00% Perhydrosqualene 12.00% Conservative 0.30% Perfume 0.50% Antioxidant qs 0.05% Water 100% We obtain a white, creamy cream, which acts on wrinkles and fine lines, and which can be applied daily. Composition 4: Face care cream (oil-in-water emulsion) Manganese gluconate 0.10% Mono-, glycerol distearate 2.00% Cetyl alcohol 1.50% Cetylstearyl alcohol / oxyethylenated cetylstearyl alcohol mixture 33 OE 7.00% Dimethylpolysiloxane 1.50% Vaseline oil 17.50% Conservative 0.30% Perfume 0.50% Glycerin 12.50% Water qs 100% Composition 5: facial care cream (oil in water emulsion) Walnut extract 5.00% Mono, glycerol distearate 2.00% Cetyl alcohol 1.50% Cetyl stearyl alcohol / alcohol mixture Cetyl stearyl oxyethylene 330 ^E 7.00% Dimethylpolysiloxane 1.50% Vaseline oil 17.50% Conservative 0.30% Perfume 0.50% Glycerin 12.50% Water 100% QSP

Claims (14)

Use in a composition or for the preparation of a composition an effective amount of manganese or at least one of its salts, the manganese or the composition being intended to relax and / or relax the tissue skin and / or subcutaneous. Use in a composition or for the preparation of a composition an effective amount of manganese or at least one of its salts, the manganese or the composition being intended to treat, curatively and / or preventive, wrinkles and fine lines of the skin. Use according to the preceding claim, for reducing wrinkles and fine lines. Use in a composition or for the preparation of a composition an effective amount of manganese or at least one of its salts, the manganese or the composition being intended to smooth the skin. Use in a composition or for the preparation of a composition an effective amount of manganese or at least one of its salts, the manganese or the composition being intended to attenuate and / or erase the micro-relief skin. Use according to claim 1, characterized in that the relaxation and / or relaxation of the skin and / or subcutaneous tissue is a relaxation or relaxation of the muscles. Use according to any one of the preceding claims, characterized in that the manganese is used in an amount representing from 0.0001% to 10% of the total weight of the composition. Use according to any one of the preceding claims, characterized in that the manganese is used in an amount representing from 0.001% to 5% of the total weight of the composition. Use according to any one of the preceding claims, characterized in that the manganese is in ionic form or in the form of a salt or in the form of a natural, plant or microorganism extract, rich in manganese. Use according to the preceding claim, characterized in that the manganese salt is chosen from organic or inorganic manganese salts. Use according to claim 10, characterized in that the organic manganese salt is chosen from manganese gluconate or manganese carbonate or manganese acetate or manganese citrate or manganese oleate or manganese oxalate . Use according to claim 10, characterized in that the inorganic manganese salt is chosen from mineral salts such as manganese chloride or manganese borate or manganese nitrate or manganese phosphate or manganese sulfate. Method for the cosmetic treatment of wrinkles and / or fine lines, consisting in apply topically a cosmetic composition comprising in a physiologically acceptable medium an effective amount of manganese or at least minus one of its salts, Process according to the preceding claim, characterized in that the manganese is in ionic form or in the form of a salt or in the form of a natural, vegetable or microorganism extract, rich in manganese.